FOXP3

Forkhead box P3
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3QRF, 4WK8
Identifiers
Symbols	FOXP3 ; AIID; DIETER; IPEX; JM2; PIDX; XPID
External IDs	OMIM: 300292 MGI: 1891436 HomoloGene: 8516 GeneCards: FOXP3 Gene
Gene ontology Molecular function • sequence-specific DNA binding RNA polymerase II transcription factor activity • core promoter binding • sequence-specific DNA binding transcription factor activity • RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity • transcription corepressor activity • protein binding • histone acetyltransferase binding • protein homodimerization activity • histone deacetylase binding • sequence-specific DNA binding • metal ion binding • NF-kappaB binding • NFAT protein binding Cellular component • nucleus • cytoplasm • protein complex Biological process • negative regulation of transcription from RNA polymerase II promoter • B cell homeostasis • cytokine production • myeloid cell homeostasis • CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment • T cell mediated immunity • tolerance induction to self antigen • regulation of T cell anergy • positive regulation of T cell anergy • negative regulation of chronic inflammatory response • negative regulation of T cell cytokine production • positive regulation of peripheral T cell tolerance induction • chromatin remodeling • regulation of transcription, DNA-templated • transcription from RNA polymerase II promoter • negative regulation of cell proliferation • response to virus • anatomical structure morphogenesis • cell differentiation • negative regulation of histone deacetylation • negative regulation of NF-kappaB transcription factor activity • negative regulation of interferon-gamma production • negative regulation of interleukin-10 production • negative regulation of interleukin-17 production • negative regulation of interleukin-2 production • negative regulation of interleukin-4 production • negative regulation of interleukin-5 production • negative regulation of interleukin-6 production • negative regulation of tumor necrosis factor production • positive regulation of interleukin-4 production • negative regulation of CREB transcription factor activity • positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation • positive regulation of transforming growth factor beta1 production • positive regulation of immature T cell proliferation in thymus • positive regulation of histone acetylation • negative regulation of histone acetylation • negative regulation of cytokine biosynthetic process • T cell activation • negative regulation of T cell proliferation • T cell homeostasis • negative regulation of sequence-specific DNA binding transcription factor activity • negative regulation of interferon-gamma biosynthetic process • negative regulation of interleukin-2 biosynthetic process • negative regulation of transcription, DNA-templated • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • negative regulation of activated T cell proliferation • negative regulation of isotype switching to IgE isotypes • regulation of isotype switching to IgG isotypes • negative regulation of cytokine secretion • negative regulation of immune response • T cell receptor signaling pathway • negative regulation of T-helper 17 cell differentiation Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE FOXP3 221333 at tn.png
File:PBB GE FOXP3 221334 s at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	50943	20371
Ensembl	ENSG00000049768	ENSMUSG00000039521
UniProt	Q9BZS1	Q99JB6
RefSeq (mRNA)	NM_001114377	NM_001199347
RefSeq (protein)	NP_001107849	NP_001186276
Location (UCSC)	Chr X: 49.25 – 49.26 Mb	Chr X: 7.58 – 7.6 Mb
PubMed search	[1]	[2]

FOXP3 (forkhead box P3), also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator (transcription factor) in the development and function of regulatory T cells. Regulatory T cells generally turn the immune response down. In cancer, an excess of regulatory T cell activity can prevent the immune system from destroying cancer cells. In autoimmune disease, a deficiency of regulatory T cell activity can allow other autoimmune cells to attack the body's own tissues.

While the precise control mechanism has not yet been established, FOX proteins belong to the forkhead/winged-helix family of transcriptional regulators and are presumed to exert control via similar DNA binding interactions during transcription. In regulatory T cell model systems, the FOXP3 transcription factor occupies the promoters for genes involved in regulatory T-cell function, and may repress transcription of key genes following stimulation of T cell receptors.

Structure

The human FOXP3 genes contain 11 coding exons. Exon-intron boundaries are identical across the coding regions of the mouse and human genes. By genomic sequence analysis, the FOXP3 gene maps to the p arm of the X chromosome (specifically, Xp11.23).

Physiology

The discovery of Foxp3 as a specific marker of natural T regulatory cells (nTregs, a lineage of T cells) and adaptive/induced T regulatory cells (a/iTregs) gave a molecular anchor to the population of regulatory T cells (Tregs), previously identified by non-specific markers such as CD25 or CD45RB.

In animal studies, Tregs that express Foxp3 are critical in the transfer of immune tolerance, especially self-tolerance. The induction or administration of Foxp3 positive T cells has, in animal studies, led to marked reductions in (autoimmune) disease severity in models of diabetes, multiple sclerosis, asthma, inflammatory bowel disease, thyroiditis and renal disease. Human trials have produced weaker results.

Unfortunately, recent T cell biology investigations revealed that T cell nature is more plastic than initially thought. Thus regulatory T cell therapy may be risky, as the T regulatory cell transferred to the patient may reverse and become another proinflammatory T cell. T helper 17 (Th17) cells are proinflammatory and are produced under similar environments as a/iTregs. Th17 cells are produced under the influence of TGF-β and IL-6 (or IL-21), whereas a/iTregs are produced under the influence of solely TGF-β, so the difference between a proinflammatory and a pro-regulatory scenario is the presence of a single interleukin. IL-6 or IL-21 is being debated by immunology laboratories as the definitive signaling molecule. Murine studies point to IL-6 whereas human studies have shown IL-21.

Pathophysiology

In human disease, alterations in numbers of regulatory T cells – and in particular those that express Foxp3 – are found in a number of disease states. For example, patients with tumors have a local relative excess of Foxp3 positive T cells which inhibits the body's ability to suppress the formation of cancerous cells. Conversely, patients with an autoimmune disease such as systemic lupus erythematosus (SLE) have a relative dysfunction of Foxp3 positive cells. The Foxp3 gene is also mutated in the X-linked IPEX syndrome (Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked). These mutations were in the forkhead domain of FOXP3, indicating that the mutations may disrupt critical DNA interactions.

In mice, a Foxp3 mutation (a frameshift mutation that result in protein lacking the forkhead domain) is responsible for 'Scurfy', an X-linked recessive mouse mutant that results in lethality in hemizygous males 16 to 25 days after birth. These mice have overproliferation of CD4⁺ T-lymphocytes, extensive multiorgan infiltration, and elevation of numerous cytokines. This phenotype is similar to those that lack expression of CTLA-4, TGF-β, human disease IPEX, or deletion of the Foxp3 gene in mice ("scurfy mice"). The pathology observed in scurfy mice seems to result from an inability to properly regulate CD4⁺ T-cell activity. In mice overexpressing the Foxp3 gene, fewer T cells are observed. The remaining T cells have poor proliferative and cytolytic responses and poor interleukin-2 production, although thymic development appears normal. Histologic analysis indicates that peripheral lymphoid organs, particularly lymph nodes, lack the proper number of cells.

Role in cancer

In addition to FoxP3's role in regulatory T cell differentiation, multiple lines of evidence have indicated that FoxP3 play important roles in cancer development.

Down-regulation of FoxP3 expression has been reported in tumour specimens derived from breast, prostate, and ovarian cancer patients, indicating that FoxP3 is a potential tumour suppressor gene. Expression of FoxP3 was also detected in tumour specimens derived from additional cancer types, including pancreatic, melanoma, liver, bladder, thyroid, cervical cancers. However, in these reports, no corresponding normal tissues was analyzed, therefore it remained unclear whether FoxP3 is a pro- or anti-tumourigeneic molecule in these tumours.

Two lines of functional evidence strongly supported that FoxP3 serves as tumour suppressive transcription factor in cancer development. First, FoxP3 represses expression of HER2, Skp2, SATB1 and MYC oncogenes and induces expression of tumour suppressor genes P21 and LATS2 in breast and prostate cancer cells. Second, over-expression of FoxP3 in melanoma, glioma, breast, prostate and ovarian cancer cell lines induces profound growth inhibitory effects in vitro and in vivo. However, this hypothesis need to be further investigated in future studies.

See also

• Autoimmune regulator (AIRE)
• Autoimmunity
• Central tolerance
• Immunity
• Lymphocytes
• Thymocyte

External links

• GeneReviews/NIH/NCBI/UW entry on IPEX Syndrome
• FOXP3 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)